Patients with pulmonary tuberculosis (TB), who have been treated and cured, are epidemiologically and/or immunologically susceptible to recurrent TB episodes. Recurrent TB is associated with risk of developing drug-resistant (MDR-TB) disease, which carries a massive burden of morbidity and mortality. South Africa spends half its TB control budget on drug-resistant TB. Vaccination of TB patients to prevent recurrent TB would be a simple preventive intervention, which would have major global health impact on the burden of TB control. This R34 planning grant will support preparation for a clinical trial of a ne TB vaccine (MVA85A), given for prevention of recurrent TB disease in HIV-uninfected adult TB patients, who have successfully completed treatment. MVA85A has been studied in 19 human clinical trials and no serious complications related to MVA85A vaccination have been reported in HIV uninfected adults. The immune response to MVA85A is thought to be important for protection against TB. A team of experienced TB researchers will conduct the trial at 3 sites in South Africa, where recurrent TB is very common (18,000 cases were reported in 2010). The primary aims of the trial are to test the safety and immunogenicity of MVA85A vaccination in this study population. 850 patients with culture-confirmed, drug-sensitive, pulmonary TB will be closely monitored from enrolment until completion of a 6-month course of first-line, standard-of-care TB treatment. Cure will be confirmed by negative sputum TB cultures. Subjects will be randomized to receive either MVA85A or placebo by double-blind intradermal injection. Local and systemic adverse events, and antigen-specific T cell responses and gene expression signatures, will be measured post vaccination. A Safety Monitoring Committee will review safety data from an initial Safety Group, before proceeding to vaccinate the remaining trial subjects. The secondary aims of the trial are to identify correlates of risk and protection, and to test the protective efficacy of MVA85A vaccination against recurrent TB. Our preliminary results suggest that signatures of inflammation and the interferon response predict risk of TB disease. In blood samples collected at the end of TB treatment, we will measure gene expression by RNA sequencing and antigen-specific T cell responses by multiparameter flow cytometry, to delineate predictive signatures of TB risk. Subjects will be followed up for 1 year after vaccination to identify and treat recurrent TB disease. Vaccine-induced mechanisms of protection can only be studied in the setting of an efficacious vaccine, but the cost of such trials is prohibitive. Therefore, we will leverage the very high rate of recurrent TB to measure potential correlates in all subjects, using this highly efficient, cost-effective, novel study design. If MVA85A is shown t protect against recurrent TB, we will retrieve post-vaccination samples from subjects who were protected (controls), or not protected (cases), to measure gene expression and antigen-specific T cell responses, in order to identify correlates of MVA85A vaccine-induced protection against TB that might also be applied to other vaccine candidates.